Tetrachloroethylene (perchloroethylene, PCE) is a solvent commonly used in metal degreasing, textile processing, and dry cleaning. Because it is often used in poorly controlled settings, it is a common ground water and Superfund site contaminant. PCE has well-documented neurotoxic effects in highly exposed adults and there is increasing evidence for neurotoxic effects in prenatal and childhood exposures, critical periods of vulnerability for the developing nervous system. Our prior research found that early life exposure to PCE- contaminated drinking water was associated with substance abuse during adolescence and adulthood. However, early life exposure to social stressors is widely thought to influence this behavior, and we had limited information about how social stressors may have contributed to these associations. Thus, the proposed retrospective cohort study will examine early life exposure to PCE and social stressors, alone and in combination, to confirm and extend earlier results. Specifically, the proposed research will examine: (1) the dose-response relationship between early life exposure to PCE-contaminated drinking water and substance use (i.e. illicit drug use and unhealthy alcoholic beverage consumption) during adolescence and adulthood, (2) the dose-response relationship between early life exposure to social stressors (i.e. household dysfunction, child abuse and neglect) and substance use during adolescence and adulthood, and (3) how the relationship between early life exposure to PCE-contaminated drinking water and subsequent substance use is modified by early life exposure to social stressors. The study population will be a cohort of 4,000 individuals with prenatal and early childhood exposure to PCE-contaminated drinking water and a comparable group of 4,000 unexposed individuals born in Massachusetts and Rhode Island between 1969 and 1983. By using an interdisciplinary approach to assess a mixture of chemical and social stressors during a susceptible life stage, the findings will improve our understanding of the role of a common neurotoxin in the complex etiology of substance use, a condition associated with substantial morbidity and mortality in the US. The findings will also assist policy makers in determining exposure limits that protect pregnant women and young children, ensuring that US drinking water supplies are safe for all consumers.